(1) Cerebral metabolism was studied in relation to age and drug resposes in unanesthetized rats. The regional cerebral metabolic rate for glucose (rCMRglc) as measured with 14C-2-deoxy-glucose, increased between 1 and 3 months when the rat brain continues to grow, but remained unchanged during senescence, suggesting that compensatory mechanisms in the brain can maintain resting function. 2) Cerebral metabolic rates for oxygen and glucose, as well as cerebral blood flow, were unrelated to age in awake Fischer-344 rats, indicating that coupling between flow and metabolism is maintained during aging of the rat brain. 3) In adult rats, central muscarinic stimulation with oxotremorine increased rCMRglc in brain areas involved in motor and cognitive function, but the pattern was more general than expected from receptor distribution. 4) Metabolic responses to agonist and antagonist drugs of Gamma-aminobutyric acid (GABA), a central inhibitory neurotransmitter, were not correlated with markers for GABAergic synapes, indicating that additional factors such as neural circuitry determine complex responses to drugs. GABA agonists generally decreased rCMRglc, but produced a relative increase in the dentatorubro-thalamic pathway. 5) The pharmacodynamic metabolic respose to haloperidol, a dopaminergic antagonist, was related to dose and time after administration, and interpreted in terms of demonstrated pharmacokinetics of this drug. 6) A quantitative method was developed to examine incorporation of plamitate from plasma to brain as a measure of brain lipid metabolism. Regional incorporation was correlated generally with rCMRglc, and was greater in cerebral gray and white matter regions. Brain palmitate uptake decreased in Fischer-344 rats between 1 and 3 months of age, but remained unchanged after 3 months. 7) Although ketone bodies (3-hydroxybutyrate and acetoacetate) can partially replace glucose as substrates for brain oxidative metabolism, severe hyperketonemia in resting rats did not reduce calculated rCMRglc.